WO2001034290A2 - Dispositif pour la synthese, le criblage et la caracterisation a haut rendement de banques combinatoires, et procedes de fabrication du dispositif - Google Patents

Dispositif pour la synthese, le criblage et la caracterisation a haut rendement de banques combinatoires, et procedes de fabrication du dispositif Download PDF

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Publication number
WO2001034290A2
WO2001034290A2 PCT/US2000/030722 US0030722W WO0134290A2 WO 2001034290 A2 WO2001034290 A2 WO 2001034290A2 US 0030722 W US0030722 W US 0030722W WO 0134290 A2 WO0134290 A2 WO 0134290A2
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Prior art keywords
array
silicon
wells
well
membrane
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PCT/US2000/030722
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English (en)
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WO2001034290A9 (fr
WO2001034290A3 (fr
Inventor
Christopher D. Tagge
Robert B. Wilson, Jr.
Seajin Oh
Albert Hirschon
Marianna F. Asaro
Michael J. Coggiola
Ron Pelrine
Dale Ploeger
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Sri International
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Priority to AU14766/01A priority Critical patent/AU1476601A/en
Publication of WO2001034290A2 publication Critical patent/WO2001034290A2/fr
Publication of WO2001034290A3 publication Critical patent/WO2001034290A3/fr
Publication of WO2001034290A9 publication Critical patent/WO2001034290A9/fr

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    • G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
    • G01N25/48—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation
    • G01N25/4846—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation for a motionless, e.g. solid sample
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    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
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    • B01L3/50853—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates with covers or lids
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Definitions

  • This invention relates to a workstation, apparatus and methods for the high- throughput synthesis, screening and/or characterization of combinatorial libraries.
  • the invention includes a workstation, an array, a covered array, and an apparatus comprising the array, as well as methods for using and making these. These methods include the use of an array, which may be transferred between a series of different synthesis, screening, or characterization stations.
  • combinatorial techniques to generate libraries of chemical and/or biological compounds is known in the art. Once these libraries have been generated, it is necessary to screen or characterize the compounds to determine if the desired properties are present, i.e. physical, chemical and/or biological properties, for example.
  • desired properties i.e. physical, chemical and/or biological properties, for example.
  • most techniques developed for screening and characterization of combinatorial libraries are sequential, involve sample preparation or sample transfer steps, and are generally labor-intensive, time-consuming and expensive for large libraries or arrays of several compounds.
  • WO 97/37953 describes mass-based encoding and qualitative analysis of combinatorial libraries, these techniques are used primarily as a means for encoding, and are not adapted to quantitative analysis of the comonomer content of compounds or incorporation of a reagent, for compounds synthesized in combinatorial libraries.
  • Polymer composition has not been investigated using radiography. Cracks and formations in polymer films have been investigated by diffusing a radiolabeled gas or liquid into a preformed polymer and scanning the sample using radiography. (See e.g., Figge, K. et al., Deut.
  • Radiography has been used extensively for the rapid screening of biological samples. Yet, radiography has not been generally extended for the analysis of a variety of compounds.
  • polymer compositions e.g., comonomer content
  • comonomer content have never been investigated using radiography. Therefore, what is needed in the art is a technique for screening and characterization of combinatorial libraries that provides a qualitative and/or quantitative determination of comonomer content or incorporation of a reagent. This invention answers this need.
  • Adapting these combinatorial chemistry techniques to the microscale is particularly a challenge in fields such as catalysis and polymer chemistry.
  • Catalytic olefin polymerization for example, is sensitive to small variations in conditions and has rarely been attempted using microscale combinatorial techniques.
  • microscale combinatorial techniques could be adapted for use in these fields, this would significantly facilitate research and development, with the advantages of lower reagent costs, higher throughput, and greater efficiency.
  • WO 98/035221 The combinatorial synthesis and analysis of supported and unsupported organometallic compounds and catalysts (e.g. homogeneous catalysts) has been described in WO 98/03521.
  • the substrate has an array of materials fixed thereon and the detector has X-Y motion.
  • the detector is fixed and the substrate having an array of materials thereon has R- ⁇ motion.
  • WO 98/15969 describes mass spectrometry and methods for rapid screening of libraries of different materials. However, for large combinatorial libraries, these sequential methods can be time-consuming and expensive. In addition, these methods are not adapted such that the compounds could be synthesized in the same array used for analysis.
  • This invention relates to a workstation, apparatus, and methods for high- throughput synthesis, screening and characterization of individual compounds in combinatorial libraries.
  • the invention also relates to an array having a plurality of wells, an apparatus comprising the array, or an automated workstation where the same array is moved between several different analytical instruments or stations, as well as methods for using these.
  • the invention relates to an array which may be directly transferred between synthesis, screening, and characterization stations or instruments, preferably without requiring sample handling, sample preparation, or sample transfer steps.
  • the synthesis, screening, and characterization steps are carried out in a highly parallel manner, such that more than one compound is synthesized, screened and/or characterized at a time.
  • the array is also easily adapted to the microscale for several different types of reactions, including catalytic and polymerization reactions.
  • the array has thermal channels, which may be metalized or doped, and are used to provide control of the thermal conditions within a well.
  • the thermal channels may be present in a variety of arrangements. For example, at least one thermal channel may be aligned parallel to at least one of the rows or columns. In some embodiments, there may be two thermal channels on either side of the row of wells. It is also possible to provide different temperature ranges to different thermal channels.
  • the thermal channels are arranged in an array of rows and columns and the thermal channels define a checkerboard pattern around the wells; this arrangement is often used to provide isothermal conditions for synthesis or analysis.
  • the bottom of the wells comprises a membrane layer, which is flexible, thermally conductive, or gas-permeable.
  • the membrane will typically comprise at least one material selected from the group consisting of: silicon, doped silicon, silicon dioxide, doped silicon dioxide, steel, sapphire, a glass material, a ceramic material, or a plastic material.
  • the membrane will comprise at least one material selected from silicon, doped silicon, steel, silicon nitride and silicon oxynitride.
  • the membrane will comprise at least one material selected from silicon and doped silicon.
  • the dopant is preferably boron, phosphorus, or arsenic.
  • the membrane layer will typically be of a substantially uniform thickness. For instance, the membrane may have a thickness from about lOOnm to about l ⁇ m, from about l ⁇ m to about 50 ⁇ m, or from about I ⁇ m to about 20 ⁇ m.
  • the array comprises thermal channels and the wells in the array further comprise a membrane forming a layer at the bottom of the well.
  • the features of the thermal channels and the membrane layer are as described in other embodiments, and any additional features of any other embodiment, either taken alone, or in combination may be incorporated.
  • this invention applies generally to both arrays of compounds or mixtures of compounds in combinatorial libraries. There may be individual compounds in each well, or mixtures of compounds. Moreover, the invention is not limited to fields such as pharmaceutical research, biotechnology, and agro chemistry, but may also be applied to a number of fields, including but not limited to, fields involving polymers, catalysts, superconductors, zeolites, magnetic materials, phosphors, thermoelectric materials, and high and low dielectric materials.
  • This invention relates to apparatus and methods for the high-throughput synthesis, screening and/or characterization of combinatorial libraries.
  • the invention relates to an array, a covered array, and/or an apparatus comprising the array. These apparatus are designed such that the array can be transferred between synthesis, screening and/or characterization operations, without requiring sample transfer from the array, or excessive sample preparation steps.
  • the synthesis, screening, and/or characterization is carried out in a highly parallel fashion, where more than one compound or component of the library is synthesized, screened, and/or characterized at the same time.
  • the invention is adapted to the microscale.
  • the invention also relates to a covered array, comprising the array and an array cover, as well as an apparatus comprising the array, which comprises the array, an array cover and a stage.
  • the array, array cover, and the stage may be interchanged or modified as needed for a particular application.
  • the invention also relates to a variety of methods for a combinatorial chemistry process, screening, and characterizing. In the combinatorial chemistry process, combinatorial libraries are synthesized in the array. After synthesis, the array may then be transferred to a number of screening and/or characterization stations.
  • the invention is not limited to compounds synthesized in the array.
  • methods of the invention are not limited only to compounds synthesized in the array.
  • compounds that have been previously synthesized or purchased may be placed in the array for high-throughput screening and/or characterization.
  • the invention relates to a number of methods for the screening and/or characterization of compounds in a combinatorial library in the array.
  • the invention relates to a process for thermal imaging, where the heat generated in each well of the array is monitored in real time with a camera. This method may be used to screen and identify promising wells for further study and/or characterization.
  • the invention relates to a process for the parallel differential scanning calorimetry, where reactions may be run under isothermal conditions to obtain reaction kinetics data and thermodynamic data, for example.
  • the invention also relates to methods for measuring the viscosity, stiffness and heat deflection temperature of compounds of the array by using an electrostatic interaction to induce vibrations of the silicon membrane, which are correlated to various physical properties of the compounds in each well.
  • the invention also relates to methods for determining the incorporation of a labeled reagent into a product of the array by digital autoradiography; this method is particularly useful for techniques such as determining the co-monomer content of a polymer.
  • the invention relates to a workstation, comprising at least one stage to support at least one array, and at least one unit or analytical instrument.
  • the array comprises a substrate having a plurality of wells.
  • the unit or analytical instrument may be selected from any synthetic or analytical instrument, and is used for synthesis, screening and/or characterization of combinatorial libraries.
  • the workstation may further comprise means for transferring the array from a first analytical instrument to one or more other analytical instruments.
  • the workstation may also comprise means for transferring the array, such as a robotic hand.
  • the workstation is automated.
  • the array is bar-coded, and/or the workstation further comprises array hotels. Any of the embodiments of the invention may be used either alone or taken in various combinations. Additional objects and advantages of the invention are discussed in the detailed description that follows, and will be obvious from that description, or may be learned by practice of the invention. It is to be understood that both this summary and the following detailed description are exemplary and explanatory only and are not intended to restrict the invention.
  • FIG 1 illustrates the steps in a process for fabricating the array from a silicon wafer. This figure shows the following elements: (1) silicon wafer, (2) epitaxial layer, (3) silicon dioxide layer, (4) Si N 4 layer, (5) resist pattern, (6) thin metal film, (7) etching protective housing, (8) thermal channel, and (9) well. This process is described in greater detail in the specification.
  • FIG 2 shows a cross-section of one embodiment of the array, and a magnification of a cross section of the membrane layer.
  • the membrane layer (10) is porous, as shown.
  • FIG 3 shows a cross-section of an embodiment of the array, with the well (9) and thermal channels (8) shown.
  • the gasket (11) is also shown, as well as the location of the membrane layer (10).
  • the thin metal film (12) will also be present.
  • FIG 4 shows an embodiment of the array, where the substrate is stainless steel.
  • the wells (9) are shown, as well as holes (13) for attaching the array in an apparatus, e.g. to an array cover, by a fastener such as a screw or a bolt.
  • the well size in this figure is approximately 75 ⁇ L.
  • FIG 5 A and FIG 5B show an embodiment of the array.
  • a magnified view of the well (9) is shown in FIG 5 A.
  • FIG 5B shows a greater magnification of FIG 5 A, where the porosity of the membrane layer of the well is shown.
  • FIG 6 is a magnification of the array shown in FIG 5.
  • FIG 6 A is a magnification of the view in FIG 5B, where the porosity of the membrane layer is shown.
  • FIG 6B is a further magnification of FIG 6 A, where the porosity of the membrane layer is shown in greater detail.
  • FIG 7 shows an apparatus according to an embodiment of the invention, comprising an array having a plurality of wells (9) and a stage (14), where the stage may further comprises a gas manifold and/or means for regulating temperature or heating. Also shown are a series of holes (13) for attaching the array in an apparatus.
  • FIG 8 shows a reaction chamber for thermal imaging of polymerization catalysts. The camera mounted above the chamber is interfaced with a video recorder to monitor heat generation in real time, to produce images as shown in FIG 9.
  • FIG 9 shows an image of various solid acid and zeolite catalysts as monitored in the array.
  • the thermal image indicates that higher levels of heat generated for those wells correspond to (1) ZeolonTM which is commercially available from Norton, Worchester, MA, (2) SO ZrOz, and (3) WO 3 /ZrO 2 .
  • FIG 10 shows a cross section of an embodiment of the array used for reaction calorimetry.
  • the array comprises at least one reaction well (9), which contains a reaction mixture (22).
  • the wells comprise a thin silicon membrane forming the bottom of the well.
  • the stage (20) further comprises a heater/temperature sensor (21).
  • the array cover (19) comprises a reusable stainless steel gas manifold and, optionally, valves to inject solutions (not shown).
  • FIG 1 1 shows an embodiment of the reaction calorimeter.
  • the reaction calorimeter is composed of three sections, which may be mechanically clamped together.
  • the array cover (19) comprises an array of gas manifolds (23), which are positioned over individual wells.
  • the array comprises cooling channels (8), and gasket/gold seals (11) disposed around the edges of each well.
  • the wells further comprise a membrane layer forming the bottom of the well, and in direct contact with the stage (20).
  • the stage comprises an array of heaters/temperature sensors (24), corresponding to the wells.
  • the apparatus further comprises means, positioned over the array cover, for monitoring thermal changes from at least one well.
  • FIG 12. A cross section of an embodiment of the viscosity/stiffness sensor is shown in FIG 12.
  • the stage (25) is a proximity sensor stage, comprising a fiber optic detector, which is capable of optical detection (29).
  • An indium tin oxide (ITO) electrode (27) is used to apply alternating electrostatic potential to induce vibration of the membrane(s).
  • the sample (28) is contained in a well (9), and the bottom of the well comprises a thin silicon membrane (10) comprising a thin, reflective metal coating (12).
  • FIG 13 shows a mass spectrometry apparatus comprising an array cover (30), an array (32), a stage (14), a mass spectrometer, and means for heating the samples in one or more wells.
  • the array cover (30) comprises a gas manifold, which is in flow communication with the mass spectrometer.
  • the stage (14) comprises a porous stainless steel 316L membrane (34), a backing plate (35), a deflector plate (36), a gas inlet chamber (37), and a gas inlet (38).
  • the array (32) is in contact with the stage (14), and the stage provides a heat source to the wells of the array.
  • the array cover comprises tubes (31) leading to sampling valves which allow the products from selected microwells to be examined by the mass spectrometer.
  • FIG 14 and FIG 15 show further views of an embodiment of the invention. Also FIG 7 shows an embodiment of the invention where the array (32) and stage (14) are assembled, without the array cover.
  • the workstation incorporates a thermal imaging unit (39), a camera (44), a parallel reaction calorimeter unit (40), a parallel differential scanning calorimetry unit (41), a viscosity/stiffness sensor (42), and an oven (51).
  • the workstation is housed in a drybox/glovebox (43), and may optionally provide an inert atmosphere.
  • the workstation further comprises means for transferring the array from the first analytical instrument to a second analytical instrument. As shown in FIG 16, there may be vial rack (45), plate rack positioned outside the workstation (46), micropipetter (47), handling tool (48), plate rack positioned inside the workstation (49) and a tool rack (50) in this embodiment.
  • FIG 17 shows an overview of the combinatorial reaction well and aperture plot.
  • FIG 18 shows a sequence of operations for gas phase analysis, including the Reactant Gas Dosing Phase (FIG 18a), the Reaction Phase (FIG 18b), and the Analysis Phase (FIG 18c).
  • FIG 19 shows the conceptual description of two-dimensional time-of-flight mass spectrometry.
  • FIG 20a, FIG 20b, FIG 20c, and FIG 20d show a possible instrument configuration for analysis of combinatorial reaction products.
  • FIG 21 shows alternative configuration for using volcano field ionization sources for organic/polymer analysis.
  • FIG 22 shows a configuration for parallel bulk/surface composition analysis.
  • the invention relates to an array, which is used to generate combinatorial libraries of compounds.
  • the array comprises a substrate having a plurality of wells.
  • the substrate may be any material having a rigid or semi-rigid surface, and may be in any shape that is convenient and practical.
  • the wells and thermal channels may be in the form of dimples, wells, raised regions or etched trenches in the substrate.
  • array typically array have rows and columns in arrangements of about 8 x 12, and multiples thereof (i.e. 16 x 24, 32 x 48, etc.), or arrays of about 10 x 10, and multiples thereof (i.e. 100 x 100, 1000 x 1000, etc.).
  • the wells may also be arranged in a circular arrangement.
  • the array can be easily interchanged between different stations or analytical instruments without requiring transfer of compounds or components of the library from the array. This feature of the array reduces sample preparation and sample transfer steps.
  • the array comprises a substrate having at least one thermal channel.
  • the thermal channels may be metalized for resistive heating, or doped with a material selected from the group consisting of boron, phosphorus, or arsenic, among others.
  • the thermal channels may contain a fluid or gas, which is used to regulate the temperature.
  • the thermal channels contain a coolant, such as nitrogen, air, water, methanol, hydrocarbons, or halogenated hydrocarbons, which permits the reactions within the wells to be run at a desired temperature.
  • the reactions within each well can run under isothermal conditions.
  • the thermal channels allow for analytical analysis to be conducted under isothermal conditions.
  • the thermal channels may be aligned parallel to at least one row or column, or may define a checkerboard pattern around the wells of the array.
  • the array has at least one well that comprises a membrane, forming the bottom of the well.
  • the membrane is flexible, thermally conductive, or gas-permeable, and comprises at least one material selected from the group consisting of silicon, doped silicon, silicon dioxide, doped silicon dioxide, steel, sapphire, a glass material, a ceramic material, a plastic material, silicon nitride, silicon oxynitride, and mixtures thereof.
  • the membrane is of a substantially uniform thickness, i.e. from about 100 nm to about 1mm, from about I ⁇ m to about 50 ⁇ m, or from about l ⁇ m to about 20 ⁇ m.
  • the membrane may be used in a number of applications, including monitoring the temperature of the reaction and characterizing the product contained in the well.
  • the invention in a third embodiment, relates to an array, which has thermal channels, and where the wells of the array have a membrane layer, which is flexible, thermally conductive, and/or gas-permeable.
  • the thermal channels and the membrane layer are as has been described above in other embodiments of the invention. Any features of the other embodiments may be incorporated either alone or in combination in this third embodiment.
  • the wells of the array can have a variety of shapes, as will be evident to one of ordinary skill in the art.
  • possible shapes for the wells include any of the following: tapered rectangle, cylindrical, U-shaped, V-shaped, and rectangular.
  • the different shapes can be easily produced using standard techniques known in the art. (See K.E. Petersen, "Silicon as a Mechanical Material,” Proc. IEEE, 70(5):420-457(1982), which is hereby incorporated in its entirety.)
  • the array may be fabricated such that the wells have a volume from about InL to about 500 ⁇ L, depending upon the choice of material, as will be evident to one of ordinary skill. With other materials, the volume of the well may be greater than 1 mL. However, it is also possible to adapt the array to the microscale. Advantages of the microscale include smaller reactor volume, lower costs for reagents and labor, and generally higher throughput.
  • the wells can be fabricated to have a volume of less than about l ⁇ L.
  • the array may comprise wells having a volume of from about InL to about 500 ⁇ L, from about 0.1 ⁇ L to about 100 ⁇ L, or from about 0.25 ⁇ L to about 10 ⁇ L.
  • the array is fabricated from a substrate, typically comprising one or more materials selected from silicon, doped silicon, silicon dioxide, doped silicon dioxide, steel, sapphire, glass materials, ceramic materials and plastic materials. It is also possible to have an array comprising a hybrid substrate, with different sections made from different materials. For instance, it may be desirable to bond together a glass plate having wells and channels machined and/or etched therein, with a silicon wafer that forms the bottom of the wells. Other acceptable materials will be evident to one of ordinary skill in the art. For instance, acceptable materials for the array also include a variety of materials, such as but not limited to: Pyrex, quartz, resins, carbon, metals, or inorganic crystals.
  • suitable materials for the array include steel and steel alloys, including materials such as stainless steel.
  • a variety of ceramic materials, such as silicon nitride, silicon oxynitride, aluminum nitride, boron nitride, aluminum oxide, zirconium oxide, silicon carbide, lithium aluminum silicate and mixtures thereof may also be used.
  • plastic materials are also well suited for the fabrication of the array.
  • Typical plastic materials comprise at least one of polyethylene, polypropylene, polystyrene, polycarbonates, polyimides, poly(vinyl chloride), fluorinated polymers (for example, such as tetrafluoroethylene fluorocarbon polymers and fluorinated ethylene-propylene resins), acrylic, and poly(ethylene terephthalate).
  • suitable materials will be apparent to one of ordinary skill in the art.
  • a silicon wafer is used as the substrate for the array.
  • This embodiment is preferred because silicon is relatively inexpensive and abundant, and available in high standards of purity.
  • silicon-processing techniques are also easily amenable to miniaturization and have been well developed in related fields. Techniques have been developed to define and reproduce various device shapes and patterns using photolithographic techniques with high precision. (See K.E. Petersen, "Silicon as a Mechanical Material,” Proc. IEEE, 70(5):420-457(1982), which is hereby incorporated in its entirety.)
  • arrays made from silicon wafers can be efficiently batch-fabricated.
  • microfabrication technology provides a means to construct 100 virtually identical 8 ⁇ L microwells with thin membrane bottoms and a cooling system onto a single silicon wafer.
  • microreactors can be used to approximate the regulated conditions of bench-scale (or commercial) polymerizations.
  • the flat silicon surface provides for an excellent seal to prevent well cross-contamination.
  • the thin membranes provide for rapid heat transfer, enable calorimetry measurements, and provide the flexibility for viscosity/stiffness characterization.
  • the melting points and viscosities of the resulting polymers within the reaction wells can be measured in the array.
  • the arrays can be mass-produced at relatively low cost.
  • typical dopants include, but are not limited to, boron, phosphorus, and arsenic.
  • the amount of dopant used is an amount from about 10 13 atoms/cm 3 to about 10 19 atoms/cm 3 , from about 10 14 atoms/cm to about 10 atoms/cm , or from about 10 atoms/cm to about 10 atoms/cm 3 .
  • Other appropriate dopant materials and concentrations of the dopant will be evident to one skilled in the art, and is selected appropriately, depending upon the particular embodiment and application of the invention.
  • the array When the array is made from a silicon wafer, the array has the additional feature and advantage of being well adapted for single-use applications.
  • the array may be disposable or archivable. By batch-fabricating the array, the array may be produced at a cost such that it is cost-effective to dispose of the array after use, which avoids time-consuming cleaning operations and the risk of contamination.
  • the array may be archived. In this instance, it may be desirable to use an array cover to seal the array under vacuum or provide an inert atmosphere prior to storage. Archiving the libraries permits easy access to compounds for future studies or characterization.
  • the array is fabricated from a wafer, such as a silicon wafer.
  • a wafer such as a silicon wafer.
  • the term wafer includes a thin, round slice of a semiconductor material, usually comprising silicon.
  • the wafer will typically be processed through a series of steps, where it is ground to have a smooth, polished surface.
  • Silicon wafers are commercially available in a variety of forms, purity, and compositions. Such silicon wafers are commercially available from a variety of commercial sources, such as International Wafer Service, Portola Valley, California.
  • a lightly doped (100) silicon wafer (1) is used.
  • the amount of dopant in the wafer may vary depending on the etching method used, as will be apparent to one of ordinary skill in the art.
  • atoms with one less electron than silicon (such as boron), or one more electron than silicon (such as phosphorus) are introduced into the area exposed by the etch process to alter the electrical character of the silicon.
  • These areas are referred to as P-type (boron) or N-type (phosphorus) to reflect their conducting characteristics.
  • Wafers are usually fabricated in a clean, dust-free room.
  • the first step may be a pre-cleaning step using high purity, low particle chemicals.
  • An epitaxial Layer (2) may be grown, and/or the silicon wafers may be heated or exposed to ultra-pure oxygen in the diffusion furnaces under controlled conditions to form a silicon dioxide film (3) on the surface of the wafer.
  • This film will preferably have a substantially uniform thickness on the wafer from about 0.8 about 1 micrometer thick.
  • Alternative masking materials such as silicon nitride (4), may also be used.
  • Masking is a procedure for protecting one area of the wafer, while working on another. This procedure is also known as photolithography or photo-masking.
  • Masking comprises a step of applying a photoresist (5) or light-sensitive film to the wafer, giving it characteristics similar to a piece of photographic paper.
  • a photo aligner is used to align the wafer to a mask. Then intense light is projected through the mask and through a series of reducing lenses, exposing the photoresist with the mask pattern.
  • the wafer and the mask are aligned precisely prior to exposure.
  • the alignment tools used are fully automated.
  • the exposed photoresist is removed, and the wafer is baked to harden the remaining photoresist pattern.
  • the wafer is then exposed to a chemical solution or plasma (gas discharge) so that the silicon dioxide areas not covered by the hardened photoresist are etched away.
  • the photoresist is removed using additional chemicals or plasma.
  • an electrode material (6) may be deposited using a similar masking procedure.
  • the wells (9) and cooling channels (8) of the array are typically formed by etching the silicon, while placing the wafer in an etching protective housing (7) to protect the other side of the wafer.
  • etching methods including but not limited to wet etching methods. If wet etching methods are used, etching agents such as potassium hydroxide (KOH) or ethlylene diamine pyrocatechol (EDP) are used.
  • KOH potassium hydroxide
  • EDP ethlylene diamine pyrocatechol
  • the silicon etching rate for a particular etching agent at a certain temperature is determined, the depth of the well (9) and thermal channels (8) can be controlled by controlling the etching time.
  • Typical silicon etching rates are known in the art, and available in a number of handbooks. See K. Petersen, "Silicon as a mechanical material," Proc. IEE, 70(5):420- 457, 1982, which is hereby incorporated in its entirety
  • the etch-stop method is often used.
  • the membrane section of the silicon substrate is heavily doped by boron.
  • the doped section of the silicon substrate will not be substantially etched, or is only slowly etched in EDP etching solution.
  • the electrochemical technique is used.
  • the membrane section is doped such that a lightly doped p-n junction is formed between the membrane section and the other section to be removed.
  • a bias is applied during the wet-etching between the two section to stop etching in the membrane.
  • the membrane section is formed by diffusion of dopant from the silicon surface or by the epitaxial growth of a silicon thin film.
  • a third etching stop method is to use a buried oxide layer, called silicon on insulator (SOI).
  • SOI silicon on insulator
  • a thin silicon dioxide layer is formed between the membrane and bulk sections and used as an etching-stop layer.
  • the silicon on insulator structure is made by bonding two silicon wafers, one having a silicon dioxide layer on the surface, and grinding the other silicon wafer to a desired membrane thickness.
  • the thermal channels (8) are also made by etching techniques. Typically, a V- groove shape is made, and the array is then mechanically clamped with an array cover having a metal gasket to form a thermal channel. For example, a cooling medium may flow through these channels. A metal inlet is placed in the channel entry.
  • gaskets can be applied around each well, usually by depositing a thin film around the edges of the wells in the array by a combination of photolithography and thin film coating methods (i.e. evaporation or sputtering). Typical materials used for the gasket include gold and copper. The film can be further thickened by electroplating after completing the well and cooling channels. Graphite and polymers are also useful gasket materials, although these are typically used as O-rings or on a sheet patterned to match the array, which is laid on the array, rather than being microdeposited on the array.
  • FIG 2 and FIG 3 show a cross-section of the array.
  • the well (9) and thermal channels (8) are shown.
  • the gasket (11) is also shown, as well as the location of the membrane layer (10).
  • a thin metal film (12) will also be present at the bottom of the well.
  • FIG 2 and FIG 3 show a cross section of an embodiment of the array.
  • a magnification of the membrane layer, showing the porosity is shown in detail in FIG 5 A, FIG 5B, FIG 6 and FIG 6B.
  • the array can also be made from other machinable materials such as stainless steel, ceramics, or plastics.
  • FIG 4 shows an embodiment of the invention, where the array was made from stainless steel.
  • the choice of material depends on the compatibility of the reactants with the material and the temperature regime used.
  • stainless steel is a convenient choice, with 316 alloys being preferred.
  • Other alloys such as HASTOLYTM or LNCONELTM may be preferred for corrosion resistance with halides.
  • HASTOLYTM is a family of high-strength, nickel-based alloys with a high resistance to uniform corrosion and stress, while maintaining ease of welding and fabrication.
  • HASTOLYTM is commercially available from sources such as Haynes, Kokomo, IN.
  • LNCONELTM is the name for a series of corrosion-resistant alloys of nickel and chromium, and is commercially available from sources such as Inco, Huntington, WV. Ceramic materials such as alumina or silicon nitride or silicon carbide may also be used. Once machined, these materials can also be coated with inert material such as silica or metals such as gold for further corrosion resistance.
  • the invention relates to an array made from stainless steel.
  • a 3 1/8 inch x 3 7/8 inch x 5/8 inch thick stainless steel block was drilled to produce 96 wells, where the wells had a diameter of 3 mm, were drilled in an area of 1 1/2 x 2 1/8 inches, and formed by drilling an 8x12 grid of holes 3 mm in diameter.
  • the dimensions of the holes and the height of the reactor can be modified for smaller or larger wells. Typical dimensions for the wells in an array comprising stainless steel may range from 0.1 microliter to 1 mL, 5 microliter to 500 microliter, and/or 25 microliter to 100 microliter.
  • the holes taper at the bottom of the array to lead to 1 mm diameter holes at the bottom.
  • the spacing of the holes is such that they are compatible to conventional pipeters and combinatorial work stations.
  • the holes are spaced 4.5 mm apart.
  • a second block of stainless steel, of similar length and depth and corresponding holes is also used as a backing plate.
  • the hole size was 2 mm in diameter, although the hole size may be even smaller.
  • the thickness was 1/4 inch, although the thickness can be even less.
  • the thermal channels may be made by conventional drilling techniques, as will be evident to one of ordinary skill in the art.
  • a porous membrane such as a stainless steel mesh of 0.1 to 2 micron porosity is placed between the array module and backing module.
  • Gaskets consisting of a soft material, such as carbon, can be placed between the modules to insure no leakage between the modules.
  • a third module is made of similar exterior dimensions to fit underneath the backing plate. This module has a hole or holes drilled through it to allow gases to flow into the array. One side is hollowed out and a plate is fabricated over the gas flow hole to distribute the gases evenly throughout the array. All modules are polished smooth by common machining practices to assure a good fit when assembled. Screw holes are placed on the edges of all the modules so that the modules can be bolted together to form the microreactor assembly. Additional mounting holes are drilled and tapped on the top module so that an analysis module can be attached.
  • the array has wells having a flexible, thermally conductive, gas-permeable, and/or reflective membrane layer.
  • the membrane may be useful for a number of different types of analysis techniques, i.e. by measuring the response time of the membrane to such stimuli as electromagnetic vibrations or heat transfer, for example.
  • FIG 2 and FIG 3 show a cross section of an embodiment of the array. A magnification of the membrane layer, showing the porosity is shown in detail in FIG 5A, FIG 5B, FIG 6A, and FIG 6B.
  • Such arrays may be fabricated from a material such as a silicon wafer. In one embodiment, this process is substantially as shown in FIG 1, except that instead of an electrode layer, a variety of materials may be used, or in an embodiment of the invention, the electrode layer may be optional.
  • a double side polished silicon wafer is used. Doping is controlled during the growth of silicon large boules, which can then be sliced into wafers. Doping levels are measured by the resistivity and the desired level is smaller than about 100 ohm-cm.
  • the silicon wafers are commercially available, from a variety of commercial sources, such as International Wafer Service, Portola Valley, California.
  • a square shaped well having a 5mm by 5 mm entrance is made on the silicon wafer by the etching techniques described previously.
  • a number of chemical etchants for silicon are well known. See K. Petersen, "Silicon as a mechanical material," Proc. IEE, 70(5):420-457, 1982, which is hereby incorporated in its entirety.
  • an etchant such as potassium hydroxide (KOH) is used.
  • the bottom of the well is a thin membrane, formed by the following steps: producing an etch-stop layer, depositing a thin metal film or electrode layer, and etching the wells.
  • the first step, the etch-stop step is used to produce a uniform membrane thickness with good precision.
  • the KOH etching agent exhibits reduced etch rates on silicon heavily doped with boron. Therefore, the part of the substrate that is to become the membrane layer is selectively doped with boron.
  • One way to selectively dope part of the substrate is to grow a boron doped layer on the silicon, forming an epitaxial layer (2). The thickness of the epitaxial layer will determine the thickness of the membrane.
  • the eptitaxial process is further described in K. Petersen, "Silicon as a mechanical material," Proc. LEE, 70(5):420-457, 1982, which is hereby incorporated in its entirety.
  • the etch-stop method has the drawback that the boron doped silicon is etched very slowly in KOH.
  • An alternative technique is to use a buried silicon dioxide layer, which is also known as silicon on insulator (SOI). According to this technique, the buried silicon dioxide is made by bonding two silicon wafers together, one of which has a silicon dioxide layer on the surface, followed by grinding the silicon part until the desired silicon thickness is obtained. This process is further described in K. Petersen, "Silicon as a mechanical material," Proc. LEE, 70(5):420-457, 1982, which is hereby incorporated in its entirety.
  • a silicon dioxide layer (3) which is about 1 micrometer thick is thermally grown on the surface, or formed by exposing the wafer to ultra-pure oxygen in a diffusion furnace under controlled conditions.
  • the photoresist (5) is coated on the membrane side and a resist pattern is made by the photolithography process.
  • a metal film (6) is deposited on the membrane side of the silicon wafer that has the resist pattern, and then the resist is removed. This process, called the lift-off process, produces a metal film (6) or electrode material in the area where resist does not occupy.
  • the wells do not have a flexible, thermally conductive or reflective membrane layer.
  • the array is made in substantially the same manner as described above, but the electrode formation process is omitted.
  • a photoresist pattern is formed on the oxide layer of the well entrance side.
  • the oxide layer is etched using the etching solution.
  • the membrane side not being etched is protected by either coating with a very thick photoresist or using a stainless steel housing (7) that is designed such that only one side of the wafer is exposed to the KOH solution.
  • the silicon wafer is immersed into the etching solution.
  • the solution temperature is 50°C and the etching rate is about 1 micrometer per minute. This process is further described in K. Petersen, "Silicon as a Mechanical Material," Proc. IEE, 70(5):420-457, 1982, which is hereby incorporated in its entirety. In order to increase the etching rate, the temperature of the solution can be raised.
  • the etching rate is 1.4 micrometer per minute at 85°C.
  • the protective silicon dioxide layer is removed in a dilute HF solution (approximately 6 % in water).
  • Alternative materials, such as silicon nitride, may also be used as the etching protective layer.
  • the thermal channels (8) are fabricated by the same masking and etching techniques described for making the well (9).
  • the V-groove is formed and the cross section of the channel is determined by the width of the top opening area.
  • FIG 5 A and FIG 5B show an embodiment of the array.
  • a magnified view of the well (9) is shown in FIG 5 A.
  • FIG 5B shows a greater magnification of FIG 5 A, where the porosity of the membrane layer of the well is shown.
  • FIG 6 is a magnification of the array shown in FIG 5.
  • FIG 6A is a magnification of the view in FIG 5B, where the porosity of the membrane layer is shown.
  • FIG 6B is a further magnification of FIG 6 A, where the porosity of the membrane layer is shown in greater detail.
  • the array can be made of silicon and glass.
  • Wells and thermal channels are made on a glass plate by conventional machining, or "drilling".
  • the glass plate is bonded to the silicon middle section by the anodic bonding method, which is further described in K. Petersen, "Silicon as a mechanical material," Proc. FEE, 70(5):420-457, 1982, and W.H. Ko, J.T.Suminto, and
  • the covered array comprises an array, as has been described in detail above, and an array cover.
  • the array will comprise thermal channels.
  • the array will comprise wells having a membrane layer at the bottom of the wells in the array, and in another embodiment, the array will comprise thermal channels, and wells having a membrane layer at the bottom of the wells in the array.
  • the array may also be adapted to the microscale. Any of the features of described for the array may be included, either taken alone or in combination.
  • the array cover may be further adapted depending upon the application.
  • the array may comprise either an individual gas manifold or an array of gas manifolds disposed over the wells and/or the thermal channels.
  • the gas manifolds may correspond to one or more wells or thermal channels.
  • the gas manifold may be common to all wells and/or all thermal channels.
  • the gas manifold can function to provide a gas to the wells of the array, i.e. as a reagent or to provide an inert atmosphere during synthesis.
  • the gas manifold could be used to remove gaseous products from the wells during synthesis.
  • the gas manifold may be used to reduce pressure in or draw a vacuum on the wells.
  • valves to introduce liquid reagents may be present on the array cover.
  • the array cover may be designed for a variety of uses.
  • the array cover may generally provide a seal over the array.
  • the array cover may be patterned to fit over the wells and/or the thermal channels, and provide a seal for individual wells or thermal channels of the array, so as to prevent cross-contamination between wells.
  • the array cover may comprise one or more different features in various combinations, such as a gas manifold and a zinc selenide window in the same array cover to permit the array cover to perform more than one function.
  • Either of the array or the array cover may comprise a gasket, fabricated by a number of means known in the art.
  • the gaskets may be deposited to be arranged around the individual wells and/or thermal channels of the array.
  • the array cover may be patterned to match the array, and the gasket may be deposited on the array cover.
  • the gasket may comprise a wide variety of materials, which are suitable for this purpose, and are compatible with the reagents and products used in generating the libraries.
  • the gasket may comprise one or more materials selected from the group consisting of a thin metal film such as gold or carbon, a polymer material including but not limited to fluorinated polymers such as tetrafluoroethylene fluorocarbon polymers and fluorinated ethylene-propylene resins, a rubber material, an elastomer material, and mixtures of these.
  • Thin films usually have a thickness of about one atom and consist of a metal deposited on a metallic substrate either externally by vapor deposition or internally by diffusion.
  • the base metal is a material such as tungsten (for a cathode) and the film may be any of a number of other metals, such as gold, carbon, thorium, cesium, zirconium, barium, or cerium.
  • thin metal films such as gold or carbon are suitable for this purpose.
  • Other appropriate materials will be evident to one of ordinary skill in the art.
  • Elastomers are typically thermosetting high polymers having properties similar to those of vulcanized natural rubber, or uncrosslinked polyolefins that are thermoplastic. Elastomers such as styrene-butadiene copolymer, polychloroprene (neoprene), nitrile rubber, butyl rubber, polysulfide rubber, cis-l,4-polyisoprene, ethylene-propylene terpolymers, silicone rubber, polyurethane rubber and mixtures thereof may also be used. The elastomers may also be further cross-linked with sulfur, peroxides, or similar agents.
  • the array may be used in a variety of synthesis, screening, and characterization techniques.
  • the array is useful for synthesizing combinatorial libraries in the array, followed by screening and/or characterization of individual compounds in the combinatorial library without requiring sample transfer from the array.
  • These combinatorial libraries may include, but are not limited to, a wide variety of compounds such as chemical or biological compounds, polymers, catalysts, superconductors, zeolites, magnetic materials, phosphors, thermoelectric materials, and high and low dielectric materials. This invention allows for the rapid high-throughput synthesis, screening and/or characterization of individual compounds in combinatorial libraries in the same array and in an efficient and economical manner.
  • the screening and/or characterization steps may be carried out in a highly parallel, and/or a non- consumptive manner.
  • the array is adapted to the microscale.
  • the invention also relates to process for varying reactants and reaction conditions within different wells of the array, while maintaining high-throughput synthesis, screening and characterization techniques.
  • the starting materials are introduced into the array and under appropriate reaction conditions, the libraries are synthesized.
  • the array has thermal channels, which may be used to control the temperature of the reaction and provide heating or cooling as needed. In this manner, it is possible to run isothermal reactions.
  • the individual thermal channels may provide a range of temperatures in different wells of the array, thereby permitting temperature optimization and thermal characterization studies.
  • the array may be used to screen and/or characterize individual compounds in the combinatorial library, without requiring sample transfer or sample preparation steps.
  • the screening and/or characterization steps may be carried out in a highly parallel manner, where more than one compound is screened at a time. In this manner, data regarding individual compounds or components in the combinatorial library may be collected, and analyzed, i.e. for structure-activity relationships.
  • Typical screening and characterizing techniques to be used in this invention include: chemical or biological testing, mass spectrometry, reaction calorimetry, parallel reaction calorimetry, parallel differential scanning calorimetry, viscosity measurement, thermogravimetric analysis (TGA), digital autoradiography, thermal imaging, polarimetry, imaging polarimetry, infrared spectroscopy, IR imaging, reflectance spectroscopy, uv-vis spectroscopy, chemisorption, surface area (BET) measurements, uv- vis fluorescence, phosphorescence, chemiluminescence, Raman spectroscopy, near IR spectroscopy, magnetic resonance imaging, NMR spectroscopy, Electron Spin Resonance (ESR) spectroscopy, gas chromatography, high performance liquid chromatography (HPLC), gel permeation chromatography (GPC), temperature rising elution fractionization (TREF), x-ray diffraction, neutron diffraction, refractometry, circular dichroism, turbid
  • the array can also be used for the measurement of chemical and physical properties such as magnetoresistance, conductivity, porosity, solubility, hexane extractables, weatherability, uv-vis stability, scratch resistance, abrasion resistance, wetability, hardness, color, dielectric constant, moisture absorption, drying rate, solvent swelling, gloss, adhesion, heat aging, shear, stain resistance, color fastness, scrub resistance, spreadability, emulsion stability, zeta potential, and contact angle. Any one of these techniques, taken alone or in combination with other techniques may be used in the practice of the invention.
  • the array can be used for the rapid screening of olefin polymerization catalysts.
  • the array allows for the rapid screening of various polymer catalysts, the rapid synthesis of combinatorial libraries of polymers, and the characterization of combinatorial polymer libraries. These methods will allow not only for the rapid discovery of new leads in polymer and catalyst chemistry, but also for rapid optimization of leads.
  • This invention relates to tools for the synthesis, screening, and characterization of combinatorial libraries, as well as methods for the synthesis, screening and characterization of libraries or arrays of compounds, in a highly parallel manner.
  • the invention relates to an array, which is designed for the synthesis of combinatorial libraries, followed by the screening and characterization of the libraries in the array without requiring sample handling and sample transfer steps.
  • the invention also relates to a covered array, comprising the array and an array cover.
  • the array cover may be further adapted or interchanged, based on the application. For instance, after the synthesis, the array cover may be interchanged with another array cover, which is adapted for screening and/or characterization.
  • an apparatus comprising the array is also claimed.
  • the apparatus may comprise the array, and at least one of the array cover and a stage. As with the array cover, the stage is adapted for the particular application at hand. For instance, the array can be easily interchanged between different apparatus or stations, as is described in detail below.
  • the invention also relates to an apparatus comprising an array cover, an array, a stage, and optionally means for attaching the array cover, the array and the stage.
  • the array has been described in detail above, and it is to be understood that the array may have any combination of thermal channels and/or wells having a membrane layer in the bottom of the well. Various other features of the array have also been described in detail, and any of these features, taken alone or in combination may be present.
  • the array cover may also further comprise one or more gas manifolds disposed above the wells. There may be one gas manifold, common to all of the wells. Alternatively, there may be several gas manifolds corresponding to individual wells, or to specific rows or columns.
  • the array cover may have an array of gas manifolds, disposed over each of the individual wells, so as to avoid contamination.
  • the gas manifolds may be used to introduce a reagent or introduce a gas into the wells of the array, remove gaseous side-products from the wells and/or provide a vacuum to the wells.
  • FIG 7 shows an apparatus according to an embodiment of the invention, comprising an array having a plurality of wells (9) and a stage (14), where the stage may further comprises a gas manifold and/or means for regulating temperature or heating. Also shown are a series of holes (13) for attaching the array in an apparatus.
  • the array can be removed after use in a particular technique, and then moved to another apparatus and assembled, i.e. with a new stage or array cover as needed, for a subsequent synthesis, screening, and/or characterization.
  • gases may enter through the bottom of the wells. This embodiment is particularly useful for applications where the components of the array are heated, or for mass spectrometry, for example.
  • the apparatus may further comprise means for controlling the temperature of the wells.
  • Such means may be incorporated into any combination of the array cover, the array, or the stage.
  • the array may further comprise one or more thermal channels, or an array of thermal channels, which are used to regulate the temperature inside the wells.
  • the thermal channels may comprise a coolant, or the thermal channels may be metalized for resistive heating or doped with a dopant.
  • Typical dopants may be selected from the group consisting of boron, phosphorus, and arsenic, and other suitable dopants will be apparent to one of ordinary skill in the art.
  • the stage may comprise a detection means disposed below the wells and in contact with the membrane layer of the wells in the array.
  • the stage may be a detection stage, and further comprise thermocouples aligned with at least one of the wells.
  • the term thermocouple encompasses devices for measuring or monitoring heat, and includes not only a thermocouple, but also a thermister, a thermometer, and other similar devices.
  • the stage may further comprise individual temperature control of at least one well of the array. Temperature control may include heating or cooling, as well as maintaining isothermal conditions.
  • the array cover, array, stage, and/or the means for attaching the array cover, array, and stage may be adapted as needed.
  • specific embodiments of the invention are described in detail. This discussion is intended to show examples of how each of the elements of the apparatus will be adapted for various techniques or analysis. Additional objects and advantages of the invention are discussed in the description that follows, and will be obvious from that description, or may be learned by practice of the invention. It is to be understood that both this summary and the following detailed description are exemplary and explanatory only and are not intended to restrict the invention.
  • the invention relates to methods for monitoring the change in heat during a reaction for an array of compounds, and/or individual compounds within the array.
  • the heat generated during a reaction provides useful kinetic data.
  • the wells of the array comprise various reaction mixtures, and a camera is positioned above the array in order to monitor the change in heat and/or temperature of the reaction mixture as the reaction progresses.
  • the thermal imaging method involves positioning a camera mounted above the wells of the array.
  • the camera comprises a suitable detector capable of responding to the desired radiation.
  • suitable detectors for infrared radiation include MCT or PtSi detectors.
  • the camera contains an array of detectors so that all samples are examined simultaneously.
  • the camera may be selected from a variety of types of cameras.
  • the camera may be an infrared (IR) camera, ultraviolet (UV) camera, visible (Vis) camera, X-ray camera, electronic gradient camera, or any combination of these.
  • the camera is one that contains an array of detectors so that all samples are examined simultaneously.
  • the activity of a catalyst is directly proportional to the heat generated by the reaction.
  • an infrared camera it is possible to rapidly screen a two-dimensional array of catalysts, in real time to monitor the activity and lifetime of the catalysts and to estimate the kinetics of the reactions.
  • the invention relates to the use of thermal imaging for high-throughput screening of catalysts.
  • the array cover When an array cover is used, the array cover will further comprise at least one window, which is transparent to the type of radiation that is being monitored. There may be one window, or there may be an array of windows positioned over individual wells. As shown in FIG 8, the array cover provides a method of sealing the microarray to prevent gases from escaping and to allow pressurization of the system if desired.
  • the array cover is shown in FIG 8.
  • the array cover comprises a IR transparent window (15).
  • the material for the window should be selected such that it is transparent to the source of radiation.
  • zinc selenide which is transparent to infrared radiation in the range of 4000 cm “1 to 700 cm “1 and is able to withstand conditions of 300 °C and 1000 psig, was used.
  • the pressure rating is determined by the relative thickness of the material compared to the area of the window.
  • the frequency response and physical properties of windows can be obtained from optical companies such as Janos Technology, Townshend, Vermont.
  • an infrared (IR) camera is used, and the apparatus further comprises a coiled tube from which cooling liquid can be added to remove heat from the IR window as necessary.
  • Cartridge heaters will heat the samples to appropriate temperatures.
  • a channel drilled from the side to the center of the baseplate will allow the introduction (or exit) of gases.
  • channels are machined in a radial direction from the center of the hole.
  • the array consisted of a glass plate comprising 96 wells with a volume of approximately 8 microliters spaced 4.5 mm from center to center to provide for thermal and chemical isolation as well as dispensing of reagents by commercially available micropipetters.
  • FIG 8 shows a reaction chamber for thermal imaging of polymerization catalysts.
  • the catalysts are introduced into each microwell and the sample array is placed directly on the baseplate and heated to the desired temperature by controlling the cartridge heaters.
  • the reactant or reactants for the polymerization, such as ethylene are introduced through the channel in the baseplate to allow a uniform distribution of the gases.
  • the camera mounted above the chamber is interfaced with a video recorder to monitor heat generation in real time, to produce images as shown in FIG 9.
  • the thermal imaging techniques are used to filter out catalysts with little or no activity. Promising catalysts are then be screened under more rigorously controlled conditions in the parallel reaction calorimeter discussed below.
  • the thermal imaging methods described above may be used, even without a means for temperature control and for running the reactions under isothermal conditions.
  • some reactions such as catalytic polymerizations, for example, are particularly sensitive to temperature and catalyst screening is most effectively run under isothermal conditions because small deviations in temperature can have very large effects on activity or reaction products.
  • the invention relates to a parallel, high-throughput process for the synthesis, screening, and characterization of combinatorial libraries under isothermal conditions.
  • a parallel reaction calorimeter is used in a process for monitoring the array in a highly parallel fashion.
  • at least one well contains at least one compound
  • the stage comprises means for individually monitoring heat emitted from at least one well.
  • the characterizing step comprises the steps of maintaining isothermal conditions in at least one well; and monitoring the heat required to maintain isothermal conditions in the at least one well.
  • integration of the activity data allows the determination of the mass of the resulting polymers, which can then be used to determine important figures of merit in subsequent analyses.
  • the array cover comprises one or more gas manifolds, which allows for several different sets of monomer gas feeds and/or pressures to be used throughout the array.
  • the array cover is fabricated from a reusable, stainless steel gas manifold.
  • the feed gas provided by a simple olefin feed, is divided into a series of manifolds. If desired, different feed gases can be used, each connected to a different manifold so that several olefins or olefin combinations can be fed into the wells of the array.
  • the feed pressure(s) are regulated by conventional pressure gauges from the source. If necessary, microcheck valves can be positioned at the end of each manifold exit.
  • the invention further comprises means for maintaining isothermal reaction conditions in at least one well.
  • the means for maintaining isothermal reaction conditions may comprise thermal channels.
  • the array consists of a disposable array of wells traversed by cooling channels, preferably microfabricated on a silicon wafer.
  • a gold foil gasket is microdeposited around each well to prevent cross-contamination.
  • the bottom of each well comprises a very thin membrane to allow for vibration and rapid heat transfer between the sample and the stage, which comprises heater/temperature sensors.
  • the stage comprises an array of heater/temperature sensors, which provide for individual temperature control of each well.
  • Microheating and temperature sensing are modified to incorporate an integrated thermal heating/cooling system for this application. See S. Oh, W. Chu, S. Cahill, Proceedings of the 1992 Spring Meeting of the Materials Research Society, San Francisco, which is hereby incorporated by reference.
  • the microheater and temperature sensors are made by using a thin film of platinum, and the temperature ratings of the heaters are in excess of 500°C.
  • An array of microcalorimeters will analyze catalyst activity and the thermal behavior of the resulting products.
  • the reaction calorimeter provides a means to conduct isothermal reactions to produce more refined data than that from thermal imaging. Cooling channels, combined with an array of microheater/temperature sensors, will control the temperature of the reaction wells; the heat input required to maintain the reaction is monitored and associated with the exothermicity (and thus, activity) of the polymerization.
  • the preferred well size is 0.25 to 8 ⁇ L, which allows the relatively facile fabrication of reaction well arrays on silicon wafers and gives low ongoing cost.
  • much larger well sizes can be fabricated by using a glass-silicon hybrid structure, in which the walls of the reactor are glass and the bottom of the well is a thin silicon membrane.
  • FIG 10. A cross section of an embodiment of the array used for reaction calorimeter is shown in FIG 10.
  • the array comprises at least one reaction well (9), which contains a reaction mixture (22).
  • the wells comprise a thin silicon membrane forming the bottom of the well.
  • the stage (20) further comprises a heater/temperature sensor (21).
  • the array cover (19) comprises a reusable stainless steel gas manifold and, optionally, valves to inject solutions (not shown).
  • the reaction calorimeter is composed of three sections, as shown in FIG 1 1, which may be mechanically clamped together.
  • the array cover (19) comprises an array of gas manifolds (23), which are positioned over individual wells.
  • the array comprises cooling channels (8), and gasket/gold seal (11) disposed around the edges of each well.
  • the wells further comprise a membrane layer forming the bottom of the well, and in direct contact with the stage (20).
  • the stage comprises an array of heaters/temperature sensors (24), corresponding to the wells.
  • the parallel reaction calorimeter provides activity data for reactions, and in particular, for catalysts held under isothermal conditions.
  • the amount of heat input required to maintain each well at the desired temperature is inversely proportional to the activity of the catalyst. For example, polymerization reactions are exothermic; the most active catalysts will require the least heat input to maintain the desired temperature.
  • the heat input/time profile provides reaction kinetics and catalyst stability data. The temperature control results in much more reliable kinetic data than that provided by thermal imaging.
  • the parallel reaction calorimeter design provides for independent variation of catalyst, cocatalyst, solvent, monomer, and temperature within the array for optimization of reaction conditions.
  • the parallel reaction calorimeter of the invention may involve the use of an array which has wells, having a volume of about l ⁇ L to about 8 ⁇ L, where the array may contain about 100 wells, and be fabricated from silicon.
  • the invention also relates to a parallel differential scanning calorimeter.
  • the protocol is the same as for the differential scanning calorimeter described above, with the following differences:
  • the stage comprises a reference material, and a corresponding electrode
  • the sample mass may be determined from integration of activity data. However, it is to be understood that the differential scanning calorimeter could also be used independently.
  • the invention relates to methods for determining the melting point of compounds in the array.
  • the invention relates to a process where a combinatorial library is generated, and any solvents are removed by evaporation.
  • the components of the library, and a reference material are heated at the same constant rate.
  • the reference material is selected from a material that does not exhibit thermal transitions under the conditions used for the measurement, i.e. constant input of heat.
  • the reference material is located in the stage.
  • the differential scanning calorimeter technique involves heating the sample and a reference material at a constant rate and measuring the difference in heat fluxes required to keep the temperature of the sample equal to that of the reference.
  • Variation from the baseline indicates melting (endothermic) or crystallization (exothermic) within the sample.
  • the peak areas are directly proportional to the enthalpy change of the phase transitions.
  • the sample size for parallel reaction calorimeter is typically about 1 mg, or in the ranges of about 1 ng to about 100 mg, about 1 microgram to about 10 mg, or about 50 microgram to about 1 mg.
  • the parallel differential scanning calorimeter has a thermocouple monitoring a reference material, which is connected in series to the samples.
  • the stage comprises an array of heaters/temperature sensors corresponding to the wells of the array.
  • the stage comprises a reference material and heaters/temperature sensors connected in series to those of the array.
  • the heating stage comprises at least one thermocouple attached to at least one well and at least one thermocouple measuring the reference temperature of a reference compound.
  • the thermocouple measuring the reference temperature of the reference compound is attached in series to the at least one thermocouple attached to the at least one well.
  • the invention relates to a method for measuring the crystallinity of combinatorial libraries of polymers. Crystallinity is an important determinant of the utility and application of a polymer.
  • the parallel differential scanning calorimeter is used for the high-throughput analysis of polymer crystallinities. This technique is integrated with the parallel reaction calorimeter to preclude the need to weigh and transfer the polymers.
  • the invention relates to methods for determining the viscosity, stiffness, mass, and thermogravimetric properties of a combinatorial library, or of individual compounds within the library.
  • the invention relates to a non- consumptive technique for measuring the viscosity, stiffness, and heat deflection temperature of components within the array.
  • the invention thus relates to a viscosity/stiffness sensor that uses the principle of electrostatic forces to cause vibration of the thin membranes fabricated into the array.
  • the viscosity sensor is based on an electrostatic interaction to induce vibrations of the silicon membrane that forms the bottom of the reaction well.
  • the invention also relates to thermogravimetric analysis techniques. These techniques are used to measure the change in weight of a sample with rising temperature.
  • the change in temperature may be related to the evolution of a gas, for example.
  • the protocol is the same as that described for the viscosity sensor, where the change in mass of the sample affects the vibration of the membrane.
  • the amplitude of vibration of the membrane will vary with sample mass and viscosity (or stiffness). It is possible to subtract the effect of polymer mass through correlation with polymer activity data.
  • This viscosity/stiffness sensor measures the viscosity, stiffness, and heat deflection temperature of components in the array.
  • the viscosity/stiffness/mass sensor functions as a thermogravimetric analyzer, determining the change of sample mass with rising temperature.
  • the viscosity data for polymers obtained from the viscosity/stiffness/mass sensor is related to the melt flow rate of the polymer. If measurement is following reaction calorimetry, sample mass may be determined from integration of activity data. It is to be understood that the viscosity/stiffness/mass sensor may also be used independently.
  • the invention relates to an apparatus comprising an array and a stage, a means for applying a voltage across the membrane of the well and, optionally, an array cover.
  • a cross section of an embodiment of the viscosity/stiffness sensor is shown in FIG 12.
  • the stage (25) is a proximity sensor stage, comprising a fiber optic detector, which is capable of optical detection (29).
  • An indium tin oxide (ITO) electrode (27) is used to apply alternating electrostatic potential to induce vibration of the membrane(s).
  • the sample (28) is contained in a well (9), and the bottom of the well comprises a thin silicon membrane (10) comprising a thin, reflective metal coating (12).
  • each well in the viscosity/stiffness sensor is covered with a reflective metal coating, allowing for the electrostatic vibration of the well membranes.
  • the membrane is subjected to alternating electrostatic potential to cause vibrations, which can then be measured by optical detection.
  • the bottom of the microwells have a thin metal coating to enable electrostatic vibration of the membrane and, for the embodiment involving optical detection, to reflect incident light.
  • the array will comprise thermal channels and the thermal channels are used to heat the samples. The samples may also be heated by using an oven.
  • an array of proximity sensors measuring capacitive, electric, or magnetic fluctuations, detect the amplitudes of vibrations of the membranes.
  • proximity sensors measure inductive, capacitive, and magnetic changes caused by the vibrating membrane.
  • proximity sensors are commercially available from Keyence Corporation of America, Woodcliff lake, NJ.
  • a variety of proximity sensors may be used, such as but not limited to inductive gauging sensors, inductive displacement sensors, laser displacement sensors.
  • a variety of linear displacement measuring and gauging with inductive sensors are also commercially available, i.e. from Micro-Epsilon, Raleigh, NC.
  • a variety of capacitive sensors and eddy current proximity switch sensors are commercially available from Gordon Products, Inc., Brookfield, CT.
  • an optical fiber array is used to transmit and receive the light reflected from the membrane.
  • the rigid electrode must be constructed from an optically transparent material, such as indium tin oxide (ITO).
  • ITO indium tin oxide
  • the above method is applied to analyze polymers.
  • the amplitude of vibration of the membrane is affected by the polymer mass and mechanical properties.
  • the relative mass of a polymer is calculated from activity measured by reaction calorimetry. The effect of polymer mass on the data is subtracted by calculating the yield from activity data of the polymer sample.
  • the resulting viscosity data is related to the melt flow index of the polymer, which is an important indication of polymer processability.
  • the temperature By varying the temperature from ambient to above the melting point of the polymer, it will also be able to detect the heat deflection temperature or softening point of the polymers.
  • the amplitude of the vibration at temperatures below the softening point provides a measure of the stiffness the polymer.
  • the samples are heated using the thermal channels of the array.
  • the entire viscosity/ stiffness sensor is contained within an oven to enable measurements at elevated temperatures.
  • One embodiment of the invention relates to an apparatus comprising an array, an array cover, and a stage.
  • the apparatus further comprises means, positioned over the array, for measuring the radioactivity of at least one well.
  • the means for measuring radioactivity is an autoradiograph.
  • the invention relates to a process of characterizing compounds, comprising the steps of providing an array comprising compounds that have incorporated at least one radio-labeled compound.
  • the compounds may be synthesized by adding at least one compound, such as a catalyst to each well, and providing at least one radio-labeled reagent in at least one well.
  • the at least one radio-labeled reagent reacts in at least one well to form a radio-labeled compound.
  • any materials other than the compound of interest are removed, and the array is transferred to an autoradiograph.
  • the radioactivity of at least one well is then measured.
  • the radioactivity of more than one well is measured at a time, in a parallel manner.
  • Typical autoradiographs which are used in this invention include those commercially available from sources such as EG&G Berthold, Gaithersburg, Maryland. Typical models used include, but are not limited to the LB 287 Digital autoradiograph, and LB 285 and LB 284 Linear Analyzers.
  • the invention also relates to a process that further comprises the step of determining the comonomer content of a component formed in at least one well.
  • the process further comprises the step of determining the surface area or porosity of an inorganic compound in at least one well.
  • the process further comprises the step of determining the extent of tritium incorporation for the hydrogenation of an unsaturated substrate.
  • the invention is adaptable to a wide range of radiolabeled reagents.
  • the radiolabeled reagent may contain at least one of the following nuclei: 3 H, 14 C, 32 P, 35 S, 36 C1, 85 Kr, Rn, as well as others that are known in the art.
  • the invention relates to a process for the determination of comonomer content in a polymer.
  • Comonomer content of a polymer is conventionally measured through time intensive techniques such as NMR spectroscopy.
  • This invention provides a method to measure the comonomer content of a large array of copolymers simultaneously, which will reduce analysis time by two orders of magnitude compared to conventional techniques.
  • the technique of the invention provides a means for the rapid discovery of new catalysts for copolymers such as linear low density polyethylene, of which several million tons are produced every year.
  • the radiolabeled reagent may be introduced through at least one gas manifold in the array cover.
  • the array may have an array of gas manifolds, which allows for several different reagents to be introduced into each well of the array.
  • radiolabeled carbon in this scheme is indicated by the asterisk (*).
  • Monomers and labeled comonomers are then fed into a 2-dimensional array of catalysts. If the autoradiography measurement are taken following reaction calorimetry, sample mass may be determined from integration of activity data. It is to be understood that the digital autoradiograph may also be used independently.
  • Each catalyst is likely to incorporate different proportions of monomer and comonomer into the resulting polymer.
  • the array is transferred to a modified commercial digital autoradiograph.
  • the resulting digital image indicates which polymers contain the most radiolabeled comonomer.
  • the relative mass of the polymer is calculated from activity measured by reaction calorimetry. The relative comonomer reactivity ratios can then be determined for each catalyst in the array. It is to be understood that the autoradiography screen may also be used independently.
  • the invention also relates to mass spectrometry techniques adapted for combinatorial chemistry.
  • the invention relates to mass spectrometry designed for the analysis of product gases, and is typically a reaction time measurement, for example.
  • mass spectrometry is used for the analysis of solids (a product time analytical technique).
  • the mass spectrometry apparatus comprises the array cover (30), the array (32), the stage (14), a mass spectrometer, and means for heating the samples in one or more wells.
  • the array cover (30) comprises a gas manifold, which is in flow communication with the mass spectrometer.
  • the stage (14) comprises a porous stainless steel 316L membrane (34), a backing plate (35), a deflector plate (36), a gas inlet chamber (37), and a gas inlet (38).
  • the array (32) is in contact with the stage (14), and the stage provides a heat source to the wells of the array.
  • the array cover comprises tubes (31) leading to sampling valves, which allow the products from, selected microwells to be examined by the mass spectrometer.
  • FIG 14 and FIG 15 show further views of an embodiment of the invention. Also FIG 7 shows an embodiment of the invention where the array (32) and stage (14) are assembled, without the array cover.
  • the mass spectrometer can detect the molecular mass of each component eluting from the array, as well as the masses produced by a molecule when it fragments upon being ionized at the mass spectrometer ion source. In cases where masses of the various species overlaps the fragmentation pattern of the molecules can be used to help identify the identify the components.
  • mass spectroscopy for identification of organic compounds can be seen in Silverstein, et al., Spectrometric
  • the apparatus further comprises means for attaching the array cover, the array and the stage
  • the apparatus is adapted for determining the absolute molecular weight and/or molecular composition of solids within the array
  • the invention relates to the array, a mass spectrometer equipped with a robot to allow for manipulation of an array of samples in the vacuum chamber, and optionally, a means to dispense matrix elements into the array
  • the molecular weight (MW) and molecular weight distribution (MWD) of polymer samples which can have a large effect on physical properties, are determined
  • Mass spectrometry is used for the high-throughput screening of the MW and MWD of polymers This technique has the advantages of rapid analysis, microscopic sample size ( ⁇ g), and the determination of absolute MW (rather than comparison with standards)
  • an array containing polymer samples is prepared and, optionally, charged with a solution of matrix
  • the matrix and solution are typically used for MALDI, but are not required for SALI
  • the solvent is allowed to evaporate and the array is placed into a vacuum chamber equipped with a robot for manipulation of the array
  • the samples are then characterized using a mass spectrometry technique such as MALDI or SALI
  • the mass spectrometer may be used in a variety of mass spectrometry methods
  • matrix-assisted laser desorption/ionization (MALDI) of large organic molecules was introduced in 1985 by Hillekamp and coworkers for amino acids See M Karas, D Bachmann, F Hillenkamp, Anal Chem , 57 293 (1985), which is entirely incorporated by reference Since then, the field has rapidly developed and has been extended to many classes of molecules including synthetic polyolefins, such as polystyrene and poly(methylmethacrylate) having molecular weights between 1000- 100,000 and narrow MWD See H Chen, B Guo, Anal Chem , 69 4399 (1997), A T Jackson et al , J Am Soc.
  • synthetic polyolefins such as polystyrene and poly(methylmethacrylate) having molecular weights between 1000- 100,000 and narrow MWD
  • a matrix typically an aromatic alcohol or acid that absorbs at the wavelength of the laser
  • SALI Surface Analysis by Laser Ionization
  • TOF-MS time-of-flight mass spectrometry
  • Laser post-ionization can be performed either using non- resonant multiphoton ionization, or by single photon ionization (SPI).
  • SPI single photon ionization
  • TOF-MS measures the transit time of ions with a known, fixed energy over a fixed distance. This directly yields their mass- to-charge ratio, which for singly charged ions, is their atomic or molecular mass.
  • SALI laser ionization
  • a desorption beam either a laser or an ion beam, or some other form of localized vaporization
  • an ionization laser to produce positive ions from the thermally vaporized or ablated neutral molecules
  • a time-of-flight mass spectrometer to determine the mass-to-charge ratio of the laser-produced ion.
  • the SALI techniques can be extended to simultaneously perform multiple analysis in parallel using a two-dimensional detector.
  • One embodiment of the invention relates to combinatorial methods to chemically analyze new materials produced as a result of combinatorial synthesis wherein large array reaction wells are filled with varying mixtures of reactants.
  • This invention will permit the simultaneous characterization of the products formed in one row of wells.
  • a second embodiment of the invention will be used to perform simultaneous analysis of gas phase (vapor) products formed in a row of wells as a result of catalytic reactions with each well, for example.
  • An embodiment of the invention relating to a combinatorial process for performing mass spectrometric analysis of multiple solid or vapor samples in parallel is illustrated in FIG 17 through FIG 22.
  • each well As shown in FIG 17, varying amounts of selected reactants are placed in each well according to standard combinatorial practice.
  • the array (or well plate) (52) is then placed in contact with the cover, here an aperture plate (53), which may form the external vacuum wall of the time-of-flight mass spectrometer.
  • the reaction wells may be maintained at an elevated temperature to promote chemical reactions.
  • Analysis of the gas phase reaction products occurs when the sliding vacuum valve (54) is moved to expose the row of inlet apertures and the reaction array (52) is translated so as to align all wells in a single row with the corresponding apertures (55).
  • the gas phase contents of each well are admitted into the vacuum system in the form of spatially localized molecular beams that are subsequently ionized by a pulsed laser propagating just above and along the row of apertures.
  • wells (56) containing varying mixtures of selected catalyst materials are prepared and dosed with selected reagent gas at high pressure.
  • the aperture plate (53) and array (52) are separated and the sliding vacuum valve (54) is closed to preserve the high vacuum of the mass spectrometer.
  • the array (52) is moved into close contact with the aperture plate (53) to prevent communication between wells.
  • the sliding vacuum valve (54) is closed to preserve the high vacuum of the mass spectrometer.
  • the array (52) can be heated as necessary to promote reactions.
  • the analysis phase is shown in FIG 18c; the array (52) is translated with respect to the aperture plate (53) to align one row of wells with the apertures.
  • the sliding vacuum valve (54) is opened to admit any gas phase products in the row of wells into the high vacuum of the mass spectrometer.
  • a pulsed laser is directed along the row of neutral molecular beams that form as a result of the expansion of the high pressure vapors contained in each well.
  • the resulting spatially localized ion beams formed by laser ionization are analyzed by both well position and mass-to-charge ratio as shown in FIG 19.
  • the parallel ion beams formed by laser ionization of the spatially localized molecular beams are extracted and maintained parallel using appropriate electrostatic elements, then accelerated to a uniform energy.
  • the parallel ion beams pass through a pair of electrostatic deflectors upon which is impressed a time varying voltage whose timing and waveform are chosen to deflect the ions orthogonal to their flight path such that the lateral deflection is a linear function of the mass-to-charge ratio of the ions.
  • the ions Upon exiting the deflection region, the ions again traverse a field free region where they subsequently impinge upon a 2-dimensional, charge integrating detector, such as a charge-couple device (CCD).
  • a 2-dimensional, charge integrating detector such as a charge-couple device (CCD).
  • CCD charge-couple device
  • a stage (58) having the external door (57) to reaction chamber and a reactant gas inlet (59) is opened to load a array (52).
  • Combinatorial materials can be pre-deposited into wells before loading, or deposited after loading.
  • the external door (57) to reaction chamber is closed.
  • Reactant gas is admitted into reaction chamber at desired pressure.
  • the array (52) is clamped to a translating plate containing an array of apertures that are larger in diameter than the row of apertures between the reaction chamber and the vacuum chamber.
  • the array of large apertures align with the array of reaction wells.
  • the reaction wells can be heated to promote catalytic reactions.
  • the sliding vacuum valve is opened and the large aperture plate/array is translated by a motor system to align one row of reaction wells with the row of apertures in the vacuum chamber wall.
  • a pulsed ionization laser beam (61) propagates just above and along the row of spatially localized neutral vapor molecular beams (60) formed at each aperture thereby producing ions characteristics of the reaction products from each well.
  • FIG 21 An alternative configuration using volcano field ionization sources is shown in FIG 21.
  • the function of the sample entrance apertures is achieved through the use of multiple microfabricated volcano field ionization sources aligned in a row.
  • Sample vapors from a row of reaction wells is introduced into the funnel side of the volcano sources by moving the array relative to the fixed cover plate (62) containing the volcanoes until a row of wells is aligned with the row of volcanoes.
  • the volcanoes cannot be sealed on the vacuum side to maintain the low source pressure when no sample is present. Vacuum sealing would either be accomplished from the funnel side of the volcanoes, or the reaction array would be introduced into the vacuum region prior to analysis.
  • Sample vaporization can be achieved by thermal means on a row-by-row basis using heating elements such as thermal channels integral to the array, or heating elements in the stage, or heating elements incorporated into a separate plate that contacts the array from the non-well side.
  • FIG 22 Parallel TOFMS for Bulk/Surface composition analysis is shown in FIG 22.
  • the vaporization/ablation process is separated from the ioninzation process as the SALI approach.
  • a pulsed laser for example, can be directed through a series of properly oriented reflectors onto multiple vaporization sites (reaction wells) simultaneously.
  • the resultant neutral vapor plumes will be spatially localized for a time sufficiently long that a second pulsed laser propagating just above and along the row of wells will simultaneously produce ions of characteristic mass-to-charge ratios from the neutral vapors in each plume.
  • the resultant spatially localized, parallel ion beams are then extracted, separated, detected, and analyzed using the methods described in FIG 19.
  • the row of wells being characterized must be maintained under the vacuum conditions typical of the source region of a laser ionization mass spectrometer.
  • the invention also relates to a combinatorial chemistry process, used for the synthesis of compounds in combinatorial libraries in a highly parallel manner.
  • combinatorial chemistry is used to create large collection of molecules, which are known as libraries, and which can be screened together.
  • Combinatorial libraries may comprise mixtures of compounds, or may comprise an array of individual compounds in each well of the array.
  • the invention relates to a process comprising the steps of providing an array, introducing at least one reagent to at least one well of the array, and reacting the reagent in at least one well to form at least one compound.
  • the array has been described in detail above.
  • the reaction may be run in an apparatus optionally comprising an array cover, an array, a reaction stage; and means for attaching the array cover, the array, and the reaction stage.
  • the array cover may comprise at least one gas manifold.
  • the array cover may further comprise at least one gas manifold.
  • the stages should further comprise means for heating, such as individual thermocouples or a heating block.
  • the reaction may proceed through solution phase chemistry, photochemistry, polymerization, by heating, by irradiating, and other methods as are known in the art.
  • the combinatorial chemistry process may involve any type of chemical reaction.
  • the chemical reactions generally involve a chemical change that occurs through a number of ways, such as, but not limited to: combination, replacement, decomposition, oxidation, reduction, ionization, combustion, polymerization, hydrolysis, hydrogenation, hydrosilylation, hydrocyanation, hydroformylation, carbonylation, isomerization, metathesis, cross coupling, hydration, dimerization, condensation, enolization, saponification, rearrangement, phase changes, changes in physical strucuture, or modifications of these.
  • the chemical reaction may also include such events as covalent interactions, ligand binding and other such reactions. This list is not meant to be inclusive. Other reactions, which are known in the art, will be evident to one of ordinary skill.
  • the compounds produced in the array may include, for example: a polymer, a catalyst, an organic compound, an amorphous material, a crystalline material, a small- molecule, a pure material, a mixture of materials, bulk materials, particles of materials, thin films, a dispersion, an emulsion, a solution, an inorganic compound, a pharmaceutical, a sol-gel, a lubricant, a biological complex, covalent network solids, ionic solids, intermetallic materials, metal alloys, ceramic materials, organometallic materials, organic polymers, composite materials, and gases.
  • the products may be of a biological nature, such as ligand-receptor, protein-protein, nucleic acid-nucleic acid, carbohydrate- protein, nucleic acid-protein complexes, various combinations of these, or others as are known in the art.
  • An embodiment of this invention relates to a combinatorial chemistry process where the temperature of the reaction can be modulated.
  • the array may contain a plurality of thermal channels for providing a set of different temperatures to different rows within the array.
  • the stage may further comprise thermocouples and means for maintaining isothermal conditions in at least one well, such as thermal channels.
  • the combinatorial chemistry process may further comprise the steps of removing the array after the synthesizing step, wherein the array contains at least one compound in at least one well, placing the well array in an analytical instrument, and screening the compounds contained in the array.
  • the analytical instrument is selected from any analytical instrument that is known in the art, including a reaction calorimeter, a differential scanning calorimeter, a viscosity sensor, a digital autoradiograph, or a mass spectrometer.
  • the array cover and the stage may need to be changed depending upon the technique to be used.
  • Typical techniques to be used in this invention include, but are not limited to: chemical or biological testing, mass spectrometry, reaction calorimetry, parallel reaction calorimetry, parallel differential scanning calorimetry, viscosity measurement, thermogravimetric analysis (TGA), digital autoradiography, thermal imaging, polarimetry, imaging polarimetry, infrared spectroscopy, IR imaging, reflectance spectroscopy, uv-vis spectroscopy, chemisorption, surface area (BET) measurements, uv- vis fluorescence, phosphorescence, chemiluminescence, Raman spectroscopy, near IR spectroscopy, magnetic resonance imaging, NMR spectroscopy, Electron Spin Resonance (ESR) spectroscopy, gas chromatography, high performance liquid chromatography (HPLC), gel permeation chromatography (GPC), temperature rising elution fractionization (TREF), x-ray diffraction, neutron diffraction, refractometry, circular dichroism,
  • the array can also be used for the measurement of chemical and physical properties such as magnetoresistance, conductivity, porosity, solubility, hexane extractables, weatherability, uv-vis stability, scratch resistance, abrasion resistance, wetability, hardness, color, dielectric constant, moisture absorption, drying rate, solvent swelling, gloss, adhesion, heat aging, shear, stain resistance, color fastness, scrub resistance, spreadability, emulsion stability, zeta potential, and contact angle. Any one of these techniques, taken alone or in combination with other techniques may be used in the practice of the invention.
  • the array may be optionally screened or characterized. If needed, any undesired side products may be removed, i.e. through evaporation, or other techniques known in the art. Then additional reagents may be added, and the next step of the synthesis may be carried out. In this manner, it may be possible to carry out a synthesis on the array, while screening and/or characterizing the intermediates as the synthesis progresses.
  • the array cover further comprises at least one gas manifold.
  • the reagents may be introduced via the gas manifold.
  • the array cover provides a desired atmosphere.
  • a catalyst is first added to the wells of the array.
  • the catalyst may be selected from a wide variety of catalysts, including heterogeneous catalysts, and homogeneous catalysts.
  • Typical catalysts include, but are not limited to: mixed metal oxides, mixed metal nitrides, mixed metal sulfides, mixed metal carbides, mixed metal fluorides, mixed metal silicates, mixed metal aluminates, mixed metal phosphates, Nobel metals, zeolites, metal alloys, intermetallic compounds, inorganic mixtures, inorganic compounds, inorganic salts, radical catalysts, cationic catalysts, anionic catalysts, organometallic catalysts and anionic coordination catalysts.
  • the catalysts may be dispensed by using a commercially available, robotic pipetter. Commercially available systems typically require 4.5 mm spacing between wells. Microfluidic apparatus may be desired for small well volumes. Initial experiments should involve control experiments to ensure that test results are not overly influenced by what position a particular catalyst occupied in the array. These control experiments depend largely on the specific apparatus and analyte but may include tests of blank wells, four identical quadrant arrays within one plate, and calibration of apparatus with known standards.
  • the monomers for polymerization may be selected from a wide variety of compounds, and include but are not limited to: ethylene, alpha-olefins such as propylene, 1-butene, 1-pentene, 1-hexene, and 1-octene, vinyl monomers such as vinyl chloride, vinyl acetate, vinyl acrylate, methylmethacrylate, methyl vinyl ether, ethyl vinyl ether, carbon monoxide, norbornene, bisphenol A, terephthalic acid, and acetonitrile.
  • Typical oxidation substrates may include: methane, ethylene, ethane, propylene, propane, butene, butane, benzene, carbon monoxide.
  • the invention relates to a number of methods for the screening and characterization of chemical compounds in libraries or arrays.
  • a typical process involves the steps of providing an array, placing the array on a stage of a first analytical instrument and screening and/or characterizing the compounds in the array.
  • the array has been described in detail above.
  • the array contains at least one compound in at least one well; for instance, there may be one compound in each well of the array, or each well may contain a mixture of compounds or reaction products. Individual compounds in the array, or the entire array as a whole, may be screened and characterized.
  • a first analytical instrument may be selected, in order to screen and/or characterize the compounds in the array.
  • the compounds of interest may be identified in particular wells, and then the array be removed from the first analytical instrument and placed into a second analytical instrument for further characterization of compounds of interest.
  • the array cover and/or stage may need to be removed and replaced as appropriate for each technique.
  • the process further involves the steps of removing the array from the first analytical instrument, placing the array into a second analytical instrument, and screening and/or characterizing the compounds.
  • the array may thus be interchanged between several different stations for a variety of characterization steps. In this manner, a large amount of data on each compound in the array may be generated.
  • the compounds in the array are characterized in a highly parallel fashion, rather than sequentially.
  • the methods described above are generally used in order to accomplish the characterization of more than one well at a time.
  • the invention also relates to techniques which may be largely sequential, such as mass spectroscopy, where individual wells are analyzed well by well.
  • Typical analytical instruments include a camera, a reaction calorimeter, a parallel reaction calorimeter, a differential scanning calorimeter, a viscosity sensor, a stiffness sensor, a mass sensor, a thermogravimetric sensor, a digital radiography, and a mass spectrometer, and combinations of these.
  • the term camera is used to broadly encompass a number of devices for detecting and recording electromagnetic signals.
  • the camera comprises a suitable detector capable of responding to the desired radiation.
  • suitable detectors for infrared radiation include MCT or PtSi detectors.
  • the camera contains an array of detectors so that all samples are examined simultaneously.
  • the camera may be selected from a variety of types of cameras.
  • the camera may be an infrared (IR) camera, ultraviolet (UV) camera, visible (Vis) camera, X-ray camera, electronic gradient camera, or any combination of these.
  • IR infrared
  • UV ultraviolet
  • Vis visible
  • X-ray camera X-ray camera
  • electronic gradient camera or any combination of these.
  • the invention should not be limited to these instruments, and other possible instruments that are known in the art may also be used.
  • Typical screening and characterizing techniques to be used in this invention include, but are not limited to: chemical or biological testing, mass spectrometry, reaction calorimetry, parallel reaction calorimetry, parallel differential scanning calorimetry, viscosity measurement, thermogravimetric analysis (TGA), digital autoradiography, thermal imaging, polarimetry, imaging polarimetry, infrared spectroscopy, IR imaging, reflectance spectroscopy, uv-vis spectroscopy, chemisorption, surface area (BET) measurements, uv-vis fluorescence, phosphorescence, chemiluminescence, Raman spectroscopy, near IR spectroscopy, magnetic resonance imaging, NMR spectroscopy, Electron Spin Resonance (ESR) spectroscopy, gas chromatography, high performance liquid chromatography (HPLC), gel permeation chromatography (GPC), temperature rising elution fractionization (TREF), x-ray diffraction, neutron diffraction, refractometry, circular dich
  • the array can also be used for the measurement of chemical and physical properties such as magnetoresistance, conductivity, porosity, solubility, hexane extractables, weatherability, uv-vis stability, scratch resistance, abrasion resistance, wetability, hardness, color, dielectric constant, moisture absorption, drying rate, solvent swelling, gloss, adhesion, heat aging, shear, stain resistance, color fastness, scrub resistance, spreadability, emulsion stability, zeta potential, and contact angle. Any one of these techniques, taken alone or in combination with other techniques may be used in the practice of the invention.
  • the array can be used for the rapid screening of olefin polymerization catalysts.
  • Several techniques for the characterization of compounds in the array which are not consumptive, and allow for multiple characterization steps on the same array are possible.
  • the array allows for the rapid screening of various polymer catalysts, the rapid synthesis of combinatorial libraries of polymers, and the characterization of combinatorial polymer libraries. These methods will allow not only for the rapid discovery of new leads in polymer and catalyst chemistry, but also for rapid optimization of leads.
  • the analysis of the combined data from several screenings and/or several characterizations of the library or array provides a quick means of correlating the effects of catalyst/cocatalyst structure and reaction conditions on many aspects of polymer properties. This data provides an understanding of catalyst behavior, which will in turn lead to more rational design of catalysts and, ultimately, better polymer performance at lower cost.
  • the invention is readily amenable to incorporation of more techniques for polymer analysis and the expansion of the arrays (and corresponding decrease in reactor well size) to much larger arrays (e.g., 10,000) for higher-throughput.
  • the invention is also readily applicable to many classes of reactions and materials and different analysis applications.
  • the invention relates to a workstation, which comprises various stages, and various synthetic and analytical instruments.
  • the workstation comprises an array, which comprises a substrate having a plurality of wells, a series of stages to support the at least one array; and at least one unit, which is used in synthesis, screening, or characterization.
  • the synthesis, screening and characterization steps may all be carried out in the workstation.
  • the units may be independently selected from the following units but not limited to, which have been described in detail above: a thermal imaging unit, a parallel reaction calorimeter unit, a parallel differential scanning calorimeter unit, a viscosity sensor unit, a stiffness sensor unit, a mass sensor unit, a thermogravimetric unit, an autoradiography unit, a mass spectrometry unit, and optionally, an inert atmosphere.
  • a thermal imaging unit a parallel reaction calorimeter unit, a parallel differential scanning calorimeter unit, a viscosity sensor unit, a stiffness sensor unit, a mass sensor unit, a thermogravimetric unit, an autoradiography unit, a mass spectrometry unit, and optionally, an inert atmosphere.
  • Other units or instruments will may be included in the workstation will be apparent to one of ordinary skill in the art.
  • the workstation may be connected to other instruments.
  • the workstation may be connected to a mass spectrometer.
  • the workstation will incorporate a thermal imaging unit (39), a camera (44), a parallel reaction calorimeter unit (40), a parallel differential scanning calorimetry unit (41), a viscosity/stiffness sensor (42), and an oven (51).
  • the workstation is housed in a drybox/glovebox (43), and may provide an inert atmosphere.
  • the workstation will further comprising means for transferring the array from the first analytical instrument to a second analytical instrument.
  • the array may thus be transferred and/or interchanged between a number of units.
  • the process may also be automated or programmed. As shown in FIG 16, there may be vial rack (45), plate rack positioned outside the workstation (46), micropipetter (47), handling tool (48), plate rack inside the workstation (49) and a tool rack (50) in this embodiment.
  • vial rack 45
  • plate rack positioned outside the workstation (46), micropipetter (47), handling tool (48), plate rack inside the workstation (49) and a tool rack (50) in this embodiment.
  • different units and different analysis will be desired, as will be evident to one of ordinary skill in the art.
  • the means for transferring the array is a robotic hand.
  • the invention also includes an embodiment where the array is bar-coded, and/or where the workstation further comprising array hotels. In a preferred embodiment, the workstation is fully automated.
  • the workstation is used in the development of new polymerization catalysts to provide better performing polymers at lower cost.
  • the workstation is constructed in a sealed glovebox. If necessary, an inert (i.e., nitrogen, argon, etc.) atmosphere may be used, if the polymerization catalysts or other reagents are sensitive to oxygen and/or moisture.
  • Thermal imaging serves as a screen of catalyst activity. The activity of promising catalysts are then further analyzed in more detail, using instruments such as the parallel reaction calorimeter and mass spectrometer. The resulting polymers will then be characterized using the parallel differential scanning calorimeter, digital autoradiography, and/or the viscosity/stiffness sensor.
  • the workstation is used to accelerate the development of new polymerization catalysts.

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Abstract

Station de travail, appareils et procédés utiles pour la synthèse, le criblage et/ou la caractérisation à haut rendement de banques combinatoires. L'invention concerne un dispositif qui permet de mettre en oeuvre divers procédés de synthèse, de criblage et/ou de caractérisation, et ne nécessite pas de transfert d'échantillons à partir du dispositif. Dans une forme de réalisation préférée, les étapes de synthèse, de criblage et/ou de caractérisation sont mises en oeuvre de manière sensiblement parallèle : plus d'un composé est synthétisé, criblé et/ou caractérisé simultanément. L'invention peut être réalisée à petite échelle. Le dispositif peut comporter des canaux thermiques servant à réguler la température des cupules du dispositif. Les cupules du dispositif peuvent comporter une membrane, qui est utilisée dans divers procédés de criblage et de caractérisation. L'invention concerne aussi un dispositif couvert, qui comprend le dispositif et un couvercle associé ; et un appareil comprenant le dispositif, qui comporte le dispositif, un couvercle associé et un étage. Le dispositif, le couvercle associé et l'étage peuvent être modifiés si nécessaire pour mettre en oeuvre diverses techniques de synthèse et/ou d'analyse. Le dispositif est facilement interchangeable entre différents instruments d'analyse ; et, dans une forme de réalisation, l'invention concerne une station de travail automatisée dans laquelle le dispositif est transféré entre différents postes de synthèse, de criblage et de caractérisation. L'invention concerne également divers procédés de synthèse, de criblage et de caractérisation qui sont adaptés à la chimie combinatoire. Toute forme de réalisation de l'invention peut être utilisée seule ou dans diverses combinaisons.
PCT/US2000/030722 1999-11-09 2000-11-09 Dispositif pour la synthese, le criblage et la caracterisation a haut rendement de banques combinatoires, et procedes de fabrication du dispositif WO2001034290A2 (fr)

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PCT/US2000/030785 WO2001034291A2 (fr) 1999-11-09 2000-11-09 Station de travail, dispositif et procedes de syntheses, de criblage et de caracterisation haut rendement de bibliotheques combinatoires

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WO2001034290A3 (fr) 2001-08-09
AU1591301A (en) 2001-06-06

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